Ageing, inorganic nitrate and vitamin C : effects on markers of cardiovascular risk

Abstract

The first stage of atherosclerosis is endothelial dysfunction (ED) which occurs at sites where the endothelial cell layer is exposed to injury or stress. Nitric oxide (NO) is an important signaling molecule secreted by the endothelium which regulates function of this vascular barrier. Reduced NO availability is a hallmark of ED. In contrast, inorganic nitrate and vitamin C may boost NO availability. Data synthesis from 14 randomised controlled trials (RCTs) demonstrated that supplementation with inorganic nitrate or beetroot (a rich source of nitrate) improved flow mediated dilation (FMD) significantly. However, the improvement in FMD tended to be smaller in older, overweight/obese participants and in those with underlying cardio-metabolic disease. An umbrella review of 10 meta-analyses revealed weak evidence for an overall effect of vitamin C supplementation on biomarkers of cardiovascular disease (CVD) risk but subgroup and meta-regression analyses indicated significant benefits in participants with advanced age, higher BMI, lower vitamin C intake and higher CVD risk. In the first crossover RCT, I tested the effects of a single dose of inorganic nitrate on markers of vascular function (skin microvascular blood flow and circulatory biomarkers) in younger and older obese individuals subjected to acute hyperglycaemia. Inorganic nitrate supplementation produced greater improvements in biomarkers of inflammation (interleukin-6) and oxidative stress (3-nitrotyrosine) in older compared with younger participants. Conversely, greater improvement in biomarkers of endothelial function (P- and E-selectin) was observed in younger rather than older participants. In the second RCT, younger and older non-obese participants were supplemented with inorganic nitrate and vitamin C in a 2x2 factorial design. I found that the administration of inorganic nitrate and vitamin C, individually or combined, significantly improved blood pressure (BP), arterial stiffness and heart rate variability (HRV) indices in older participants. Moreover, inorganic nitrate significantly modified the effects of vitamin C on diastolic BP and HRV in younger participants. Finally, inorganic nitrate and vitamin C co-supplementation yielded synergistic effects on arterial stiffness, HRV indices and circulatory biomarkers. In conclusion, age, obesity and metabolic disorders modify the cardiovascular effects of inorganic nitrate and vitamin C.